|Publication number||US6521187 B1|
|Application number||US 09/489,261|
|Publication date||18 Feb 2003|
|Filing date||21 Jan 2000|
|Priority date||31 May 1996|
|Also published as||DE60118374D1, DE60118374T2, EP1181099A1, EP1181099A4, EP1181099B1, WO2001052991A1|
|Publication number||09489261, 489261, US 6521187 B1, US 6521187B1, US-B1-6521187, US6521187 B1, US6521187B1|
|Inventors||Roeland F. Papen|
|Original Assignee||Packard Instrument Company|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (180), Non-Patent Citations (21), Referenced by (89), Classifications (41), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application is a continuation-in-part of U.S. application Ser. No. 09/056,233, filed Apr. 7, 1998, U.S. Pat. No. 6,203,759, which is a conventional application of provisional U.S. Application No. 60/041,861, filed Apr. 8, 1997, and provisional U.S. Application No. 60/067,665, filed Dec. 5, 1997, which is a continuation-in-part of U.S. application Ser. No. 08/656,455, filed May 31, 1996, abandoned.
This invention relates to aspirating and dispensing small volumes of liquids. In particular, it relates to automatic aspirating and dispensing of small volumes of liquids onto porous brittle substrates.
The advances in biochemical technology have led to development of miniature reaction sites generally located on brittle, thin wafers, having hundreds of such reaction sites, each capable of holding small chemical and/or biological samples. The wafers are porous, with narrow pores extending into the wafer and generally normal to the plane of the surface. In order to deposit the sample onto a selected reaction site, the tip of the dispenser must be brought in close proximity with the wafer. Placing the tip of the dispenser close to the surface of the wafer introduces the risk of the tip touching the surface of the reaction medium. Since the reaction media are generally brittle, any contact could break the wafer and render useless all samples deposited on that wafer. If the contact does not break the wafer, the tip of the dispenser can abrade a coating on the vessel or destroy its confirmation. Contact with the wafer can also cause the liquid to spread on the surface. Therefore, there is a need for a system and method for dispensing small quantities of liquids containing biological and/or chemical substances in a precise location on brittle wafers without having to bring the dispenser tip into close proximity with the reaction site.
Another disadvantage of conventional methods for dispensing liquids onto wafers is that the drop at the end of the dispenser tip is placed in contact with the surface of the wafer. In order to deposit the sample in a precise location on the wafer, a drop of liquid is formed at the tip of the dispenser over the surface of the reaction site. The contact between the drop and the reaction site causes the drop to separate from the dispensing tip. The transfer of a drop of sample liquid in this manner is difficult to control because surface tension effects at the dispenser tip and the wafer surface affect the amount of liquid dispensed. As a result, there is a need for a method and system of precisely depositing small amounts of liquid at specific locations of a reaction medium. It is also necessary to have a means of dispensing liquids where the size of the drop is accurately controlled and not a function of the properties of the liquid and substrate.
One object of the present invention is to provide a system and method for accurately aspirating and dispensing submicroliter volumes of liquid onto a reaction site of a wafer without bringing the drop in contact with the surface of the wafer. Another object of the present invention is to provide a system and method for accurately verifying the volume of liquid dispensed onto the substrate.
Still another object of the present invention is to provide a system and method for dispensing subnanoliter droplets of liquid by ejecting them onto reaction sites with pore sizes 10 to 10,000 times smaller than the diameter of the drop.
Yet another object of the present invention is to provide a system and method for accurately depositing micron size droplets of liquid onto a porous substrate having submicron size pores.
Still another object of the present invention is to provide a system and method for ejecting droplets of liquid with diameters of less than 100 microns onto porous substrates with pore sizes 10 to 10,000 times smaller than the diameter of the drops. The size of the spot created by the drop on the substrate is only slightly larger than the diameter of the drop.
A further object of the present invention is to provide a system and method for aspirating and dispensing microvolumes of liquid onto porous reaction sites and accurately measuring the amount of liquid dispensed, regardless of the properties (e.g., viscosity or hydrophilicity) of the transfer liquid.
Another object of the present invention is to provide a system for aspirating and ejecting microvolumes of liquid containing chemically or biologically active s substances onto a porous reaction site of a wafer.
A still further object of the present invention is to provide for a real time monitoring of the dispensing of single 100 micron or smaller drops of liquid onto porous reaction sites of wafers.
Still another object of the present invention is to eject a plurality of drops of liquid onto a porous reaction site of a thin wafer.
Yet another object of the present invention is to eject onto a porous reaction site at least one small drop of liquid and measure, in real time, the volume of the dispensed liquid.
Other objects and advantages of the present invention will be apparent to those skilled in the art upon studying this application.
In accordance with one aspect of the present invention, 1 to 100 micron range drops of liquid are accurately deposited onto a porous reaction site having pores about 10 to about 10,000 times smaller than the size of the drop. The drops are dispensed by ejection from a tube using a piezoelectric element where the distance of the tip of the tube to the surface of the wafer is greater than the diameter of the drops. Accordingly, the drops do not touch the surface of the wafer prior to being ejected. Therefore, the properties of the liquid and the surface of the wafer do not affect the size of the drop that is ejected. The ejected drop forms a spot which is nearly the same diameter as that of the ejected droplet because it penetrates the narrow pores of the wafer.
In one aspect of the invention, a system and method for aspirating and ejecting subnanoliter drops of liquid onto a porous reaction site and detecting a pressure change resulting from the droplet ejection is presented. A known volume of a compressible fluid, e.g., a gas such as air, facilitates measuring small changes in system pressure which correlate to the volume of the transfer liquid which has been dispensed.
In accordance with another aspect of the present invention, a system and method for aspirating and ejecting subnanoliter drops of liquid onto a porous reaction site, detecting a pressure change resulting from ejection of a drop of a transfer liquid, and generating an electrical signal which indicates that single drops of liquid are dispensed at millisecond intervals is presented. By eliminating all compressible fluids (gases) from the liquid in the system, the ejection of picoliter size drops can be detected by the present invention. The dispensed drops are generally in the range of from about 5 to about 500 picoliters, often about 100 to about 500 picoliters. The pores of the wafer are in the submicron range.
In accordance with yet another aspect of the present invention, subnanoliter droplets of liquid are ejected onto porous sites of a thin wafer and the volume of the drops is measured in real time. Electrical signals indicating transient pressure changes in the transfer liquid upon dispensing liquid drops (in the range of from about 5 to about 500 picoliters, preferably about 100 to about 500 picoliters) can be detected when the liquid in the enclosed volume of the dispenser is connected to a liquid reservoir. As long as substantially all compressible fluids (gases) are kept out of the dispensing conduit (which communicates through a restricted passage to the liquid reservoir), the pressure sensor of the system of the present invention can detect dispensing a single drop of liquid in the range of from about 5 to about 500 picoliters, preferably about 100 to about 500 picoliters. The pressure change resulting from ejection of such a drop occurs in a time period long enough for the pressure change to be detectable, but short enough to complete the cycle before the next drop is ejected.
Other aspects of the present invention will become apparent to those skilled in the art upon studying this disclosure.
FIG. 1 is a block diagram of a system for aspirating and dispensing microvolumes of liquid onto a reaction site of a thin plate, illustrating the first embodiment of the present invention.
FIG. 2 is a schematic of a positive displacement pump illustrating an aspect of the first embodiment of the present invention.
FIG. 3 is side plan view of a microdispenser including a piezoelectric transducer.
FIG. 4 is a plan view of a porous wafer on which drops have been deposited.
FIG. 5 is a side elevational view, partially in cross section, showing a single drop of liquid being ejected onto the reaction site of a wafer in accordance with the present invention.
FIG. 6 is a cross sectional view of a drop of liquid penetrating the porous reaction site of a wafer.
FIG. 7 is a block diagram of the system for aspirating and dispensing microvolumes of liquid illustrating the second embodiment of the present invention.
FIG. 8 shows a plurality of liquid droplets deposited onto a porous substrate in accordance with the present invention.
FIG. 9 shows droplets deposited on the Anapore membrane in accordance with the present invention.
FIG. 10 is a graph of fluorescent signal from the drops deposited on the Anapore membrane as shown in FIG. 9.
The present invention relates to an application for the aspirating and dispensing apparatus described in parent application Ser. No. 09/056,233, U.S. Pat. No. 6,203,759.
Description of Wafers for Use in Present Invention
As used herein, the term “wafer” includes any object which has a porous site on at least one of its surfaces. The wafers suitable for use in connection with the present invention have sites with pore size significantly smaller than the size of the drops of liquid deposited onto the wafers. Generally, the pore size of the sites are from about 10 to about 10,000 times smaller than the diameter of the drops which are deposited thereon. If the drops of liquid are in the 10 to 100 micron range, the pore size should be in the micron or the submicron range. Wafers suitable for use in the present invention include those that have specific, defined reaction sites and whose surface is partially or wholly porous. Such wafers include membranes, slides, micromachined silicon, porous gels, and polymers. Generally, the pore size of the reaction sites are in the range of from about 0.1 to about 10 microns, preferably from about 0.25 to about 1 micron. One example of a wafer which is suitable for use in the present invention is the Anapore membrane, marketed by The Whatman Companies. Other wafers suitable for use in the present invention include the Hydrogel chip, manufactured by Packard Instrument Company, Downers Grove, Ill.
One example of such porous wafers is found in U.S. Pat. No. 5,843,767. While Example 5 of the '767 patent describes a system for depositing droplets on is porous wafers, there is no recognition of the problem discussed above by the present inventors and method disclosed herein to solve that problem.
Description of a First Aspirating and Dispensing Apparatus
The system constructed in accordance with the first aspirating and dispensing apparatus of the present invention includes a system liquid and a transfer liquid separated by a known volume of compressible fluid, e.g., a gas such as air (“air gap”). The air gap facilitates measuring small changes in pressure in the system liquid. The change in pressure is proportional to the volume of transfer liquid dispensed. One preferred system liquid is deionized water. As a result of capillary forces, each time a droplet in the microvolume dispensing range is dispensed, the transfer liquid will return to its prior position inside the microdispenser. The specific volume of the air gap will be increased proportionally to the amount of transfer liquid dispensed. The result is a decrease in pressure in the system liquid line which is measured with a highly sensitive piezoresistive pressure sensor. The pressure sensor transmits an electric signal which controls circuitry. The electric signal is converted into a digital form which is indicative of the volume of transfer liquid dispensed. An advantage of the present invention is its insensitivity to the viscosity of the transfer liquid. The pressure change in the system liquid corresponds to the microvolume dispensed, without being dependent on the viscosity of the dispensed liquid.
The first aspirating and dispensing apparatus of the present invention provides a microvolume liquid handling system which includes a positive displacement pump operated by a stepper motor, a piezoresistive pressure sensor, and an electrically controlled microdispenser that utilizes a piezoelectric transducer bonded to a glass capillary. The microdispenser is capable of rapidly and accurately dispensing sub-nanoliter (“nl”) sized droplets by forcibly ejecting the droplets from a small nozzle, this process is known as “drop-on-demand.” Specifically, the dispenser of the present invention dispenses drops in the range of from about 5 to about 500 picoliters, preferably from about 100 to about 500 picoliters.
To provide the functionality of an automated liquid handling system, the microdispensers in all preferred embodiments are mounted onto a 3-axis robotic system that is used to position the microdispensers at specific locations required to execute the desired liquid transfer protocol.
Referring first to FIG. 1, a first microvolume liquid handling system 10 is illustrated, and includes a positive displacement pump 12, a pressure sensor 14, and a microdispenser 16. Tubing 18 connects the positive displacement pump 12 to the pressure sensor 14 and the pressure sensor 14 to the microdispenser 16. The positive displacement pump 12 moves a system liquid 20 through the pressure sensor 14 and the microdispenser 16. After the system 10 is loaded with system liquid 20, an air gap 22 of known volume is provided. An amount of transfer liquid 24 is drawn into the microdispenser 16 in a manner described below. The transfer liquid 24 can contain one or more biologically or chemically active substances of interest. Preferably, the microdispenser 16 expels (or, synonymously, “shoots”) sub-nanoliter size individual droplets 26 which are very reproducible. The expelled droplets 26 of transfer liquid 24 are generally in the range of about 5 to about 500 picoliters, preferably about 100 to about 500 picoliters per droplet 26. For example, if one desires to expel a total of 9 nanoliters of transfer liquid 24, the microdispenser 16 will be directed to expel 20 droplets 26, each having a volume of 0.45 nanoliters. Droplet 26 size can be altered by varying the magnitude and duration of the electrical signal applied to the microdispenser 16. Other factors affecting droplet size include: size of the nozzle opening at the bottom of the microdispenser, pressure at the microdispenser inlet, and certain properties of the transfer liquid.
Referring now to FIGS. 1 and 2, in one preferred embodiment, the positive displacement pump 12 is an XL 3000 Modular Digital Pump, manufactured by Cavro Scientific Instruments, Inc., Sunnyvale, Calif. The positive displacement pump 12 includes stepper motor 28, stepper motor 29, and a syringe 30. The syringe 30 includes a borosilicate glass tube 32 and a plunger 34 which is mechanically coupled through a series of gears and a belt (not shown) to the stepper motor 28. Stepper motor 28 motion causes the plunger 34 to move up or down by a specified number of discrete steps inside the glass tube 32. The plunger 34 forms a liquid-tight seal with the glass tube 32. In one preferred embodiment, syringe 30 has a usable capacity of 250 microliters, which is the amount of system liquid 20 the plunger 34 can displace in one full stroke. Depending on the selected mode of operation, the stepper motor 28 is capable of making 3,000 or 12,000 discrete steps per plunger full 34 stroke. In one preferred embodiment, the stepper motor 28 is directed to make 12,000 steps per plunger 34 full stroke, with each step displacing approximately 20.83 nanoliters of system liquid 20. In one preferred embodiment, the system liquid 20 utilized is deionized water.
Digitally encoded commands cause the stepper motor 28 within the positive displacement pump 12 to aspirate discrete volumes of liquid into the microdispenser 16, wash the microdispenser 16 between liquid transfers, and control the pressure in the system liquid 20 line for microvolume liquid handling system 10 operation. The positive displacement pump 12 is also used to prime the system 10 with system liquid 20 and to dispense higher volumes of liquid through the microdispenser 16, allowing the dilution of certain system liquids. The positive displacement pump 12 can also work directly with transfer liquid 24. Thus, if desired, transfer liquid 24 can be used as system liquid 20 throughout the microvolume liquid handling system 10.
To prime the microvolume liquid handling system 10, the control logic 42 first directs a 3-axis robotic system 58 through electrical wire 56 to position the microdispenser 16 over a wash station contained on the robotic system 58. In one preferred embodiment, the microvolume liquid handling system 10 includes, and is mounted on, a 3-axis robotic system, the MultiPROBE CR10100, manufactured by Packard Instrument Company. The positive displacement pump 12 includes a valve 38 for connecting a system liquid reservoir 40 to the syringe 30. An initialization control signal is transmitted through the electrical cable 36 to the pump 12 by control logic 42. This causes the valve 38 to rotate (by means of stepper motor 29), connecting the syringe 30 with the system liquid reservoir 40. The control signal also causes the stepper motor 28 to move the plunger 34 to its uppermost position (Position 1 in FIG. 2) in the borosilicate glass tube 32. The next command from the control logic 42 causes the stepper motor 28 to move the plunger 34 to its lowermost position (Position 2 in FIG. 2) in the tube 32 and to extract system liquid 20 from the is system reservoir 40. Another command from the control logic 42 directs the valve 38 to rotate again, causing the syringe 30 to be connected with the tubing 18 that is, in turn, connected to the pressure sensor 14. In one preferred embodiment, the tubing 18 employed in the microvolume liquid handling system 10 is Natural Color Teflon Tubing, manufactured by Zeus Industrial Products, Inc., Raritan, N.J., with an inner diameter of 0.059 inches and an outer diameter of 0.098 inches. The next command from the control logic 42 to the positive displacement pump 12 causes the system liquid 20 inside the syringe 30 to be pushed into the microvolume liquid handling system 10 towards the pressure sensor 14. Because the microvolume liquid handling system 10 typically requires about 4 milliliters of system liquid to be primed, the sequence of steps described above must be repeated about 16 times in order to completely prime the microvolume liquid handling system 10.
The control logic 42 receives signals from the pressure sensor 14 through an electrical line 46. The signals are converted from an analog form into a digital form by an A/D (analog to digital) converter 44 and used by the control logic 42 for processing and analysis. In one preferred embodiment, the AID converter is a PC-LPM-16 Multifunction I/O Board, manufactured by National Instruments Corporation, Austin, Texas. At various points in the liquid transfer process described herein, the control logic 42 receives signals from the pressure transducer 14, and sends command signals to the pump 12, microdispenser electronics 51, and the 3-axis robotic system 58. Within the control logic 42 exist the encoded algorithms that sequence the hardware (robotic system 58, pump 12, and microdispenser electronics 51) for specified liquid transfer protocols, as described herein. Also within the control logic 42 are the encoded algorithms that process the measured pressure signals to verify and quantify microdispenser, perform diagnostics on the state of the microvolume liquid handling system, and automatically perform a calibration of the microdispenser for any selected transfer liquid 24.
The pressure sensor 14 detects fluctuations in pressure that occur with priming the microvolume liquid handling system 10, aspirating transfer liquid 24 with a pump 12, dispensing droplets 26 with the microdispenser 16, and washing of the microdispenser 16 with a pump 12. In one preferred embodiment, the pressure sensor 14 is a piezoresistive pressure sensor, part number 26PCDFG6G, manufactured by Microswitch, Inc., a division of Honeywell, Inc., Freeport, Ill. Also included with the pressure sensor 14 in the block diagram in FIG. 1 is electrical circuitry which amplifies the analog pressure signal from the pressure sensor. The pressure sensor 14 converts pressure into electrical signals which are driven to the AID converter 44 and used by the control logic 42. For example, when the microvolume liquid handling system 10 is being primed, the pressure sensor 14 sends electrical signals which are analyzed by the control logic 42 to determine whether they indicate partial or complete blockage in the microdispenser 16.
Once the microvolume liquid handling system 10 is primed, the control logic 42 sends a signal through electrical wire 56 which instructs the robotic system 58 to position the microdispenser 16 in air over the transfer liquid 24. The control logic 42 instructs the stepper motor 28 to move the plunger 34 down, aspirating a discrete quantity of air (air gap), e.g., 50 microliters in volume, into the microdispenser 16. The control logic 42 then instructs the robotic system 58 to move the microdispenser 16 down until it makes contact with the surface of the transfer liquid 24 (not shown). Contact of the microdispenser 16 with the surface of the transfer liquid 24 is determined by a capacitive liquid level sensing system (U.S. Pat. No. 5,365,783). The microdispenser is connected by electrical wire 55 to the liquid level sense electronics 54. When the liquid level sense electronics 54 detects microdispenser 16 contact with the transfer liquid 24 surface, a signal is sent to the robotic system 58 through electrical wire 53 to stop the downward motion.
The control logic 42 instructs the pump 12 to move the plunger 34 down to aspirate the transfer liquid 24 into the microdispenser 16. To ensure that the transfer liquid is successfully drawn into the microdispenser, the pressure signal is monitored by control logic. If a problem, such as an abnormal drop in pressure due to partial or total blockage of the microdispenser is detected, the control logic 42 will send a stop movement command to the pump 12. The control logic 42 will then proceed with an encoded recovery algorithm. Note that the transfer liquid 24 can be drawn into the microvolume liquid handling system 10 up to the pressure sensor 14 without the threat of contaminating the pressure sensor 14. Additional tubing can be added to increase transfer liquid 24 capacity. Once the transfer liquid 24 has been aspirated into the microdispenser 16, the control logic 42 instructs the robotic system 58 to reposition the microdispenser 16 above the chosen target, e.g., a microtiter plate or a wafer.
In one preferred embodiment, the microdispenser 16 is the MD-K-130 Microdispenser Head, manufactured by Microdrop, GmbH, Norderstedt, Germany.
As illustrated in FIG. 3, the microdispenser 16 consists of a piezoceramic tube 60 bonded to a glass capillary 62. The piezoceramic tube has an inner electrode 66 and an outer electrode 68 for receiving analog voltage pulses which cause the piezoceramic tube to constrict. Once the glass capillary 62 has been filled with transfer liquid 24, the control logic 42 directs the microdispenser electronics 51 to send analog voltage pulses to the piezoelectric transducer 60 by electrical wire 52. In one preferred embodiment, the microdispenser electronics 51 is the MD-E-201 Drive Electronics, manufactured by Microdrop, GmbH. The microdispenser electronics 51 control the magnitude and duration of the analog voltage pulses, as well as the frequency at which the pulses are sent to the microdispenser 16. Each voltage pulse causes a constriction of the piezoelectric transducer 60 which, in turn, deforms the glass capillary 62. The deformation of the glass capillary 62 produces a pressure wave that propagates through the transfer liquid 24 to the microdispenser nozzle 63, where one highly accelerated droplet 26 of transfer liquid 24 is emitted. The size of these droplets 26 has been shown to be very reproducible. The high acceleration of the transfer liquid 24 minimizes or eliminates problems caused by transfer liquid 24 surface tension and viscosity, thus allowing extremely small (e.g., 5 picoliter) droplets 26 to be expelled from the nozzle. Use of the microdispenser 16 to propel droplets 26 out of the nozzle circumvents problems encountered in the liquid transfer technique referred to “touchoff.” In the touchoff technique, a droplet 26 is held at the end of a nozzle and is deposited onto a target surface by bringing that droplet 26 into contact with the target surface while it is still suspended from the microdispenser 16. Such a contact process is susceptible to unacceptable volume deviations as a result of surface tension, viscosity and wetting properties of the microdispenser 16 and the target surface. The present invention avoids the problems of the contact process because the droplets 26 are expelled out of the microdispenser 16 at a velocity of several meters per second. The total desired volume is dispensed by the present invention by specifying the number of droplets 26 to be expelled. Because thousands of droplets 26 can be emitted per second from the microdispenser 16, the desired microvolume of transfer liquid 24 can rapidly be dispensed.
In one preferred embodiment, the lower section of the glass capillary 62, located between the piezoelectric transducer 60 and the nozzle 63, is plated with a conductive material, typically platinum or gold. The use of this material provides an electrically conductive path between the microdispenser 16 and the liquid level sense electronics 54. In one preferred embodiment, the glass capillary 62 has an overall length of 73 millimeters and the nozzle 63 has an internal diameter of 75 micrometers.
To dispense microvolume quantities of transfer liquid 24, analog voltage pulses are sent to the microdispenser 16, thus emitting droplets 26 of liquid. Capillary forces acting on the transfer liquid 24 replace the volume of transfer liquid 24 emitted from the microdispenser 16 with liquid from the tubing 18. Since the transfer liquid-air gap system liquid column terminates at a closed end in the positive displacement pump 12, however, there is a corresponding drop in the system liquid 20 line pressure as the air gap 22 is expanded. This may be seen in FIG. 4 of parent application Ser. No. 09/056,233 U.S. Pat. No. 6,203,759. The magnitude of the pressure drop is a function of the size of the air gap 22 and the volume of the liquid dispensed.
With an air gap 22 of known volume, the pressure change as detected by the pressure sensor 14 is proportional to the volume dispensed. Thus, from the pressure change measured by the pressure sensor 14, the control logic determines the volume of transfer liquid 24 that was dispensed. In one preferred embodiment of the present invention, depending on the properties of the transfer liquid, it is preferable that the drop in pressure not exceed approximately 30 to 40 millibars below ambient pressure. If the amount of transfer liquid 24 dispensed is sufficient to drop the pressure more than 30 to 40 millibars, the pressure difference across the microdispenser 16 (i.e., the is difference between the ambient pressure acting on the nozzle 63 and the pressure at the capillary inlet 65) will be sufficient to force the transfer liquid 24 up into the tubing 18. This will preclude further dispensing. There is a maximum amount of transfer liquid 24 that can be dispensed before the control logic 42 is required to command the pump 12 to advance the plunger 34 to compensate for the pressure drop. This maximum volume is determined by the desired dispense volume and the size of the air gap 22. Conversely, the size of the air gap 22 can be selected based on the desired dispense volume so as not to produce a pressure drop exceeding 30 to 40 millibars below ambient pressure. It is also within the scope of the present invention to advance the plunger 34 while the microdispenser 16 is dispensing, thereby rebuilding system liquid 20 line pressure so that the microdispenser 16 can operate continuously.
The change in system liquid 20 pressure is used to verify that the desired amount of transfer liquid 24 was dispensed. A second verification of the amount of transfer liquid 24 that was dispensed is made by the control logic 42 that monitors the system liquid 20 line pressure while directing the pump 12 to advance the syringe plunger 34 upwards towards Position 1. The syringe plunger 34 is advanced until the system liquid 20 line pressure returns to the initial (pre-dispense) value. Because the control logic 42 tracks the displaced volume, the plunger 34 moves (20.83 nanoliters per stepper motor 28 step) and a second confirmation of the volume dispensed is made, thus adding robustness to the system. After a second dispensing verification, the system liquid 20 line pressure is now at the correct value for the next dispensing action if a multidispense sequence has been specified.
Once the transfer liquid 24 dispensing has been completed, the control logic 42 causes the robotic system 58 to position the microdispenser 16 over the wash station. The control logic 42 then directs pump 12 and robotic system 58 in a wash protocol that disposes of any transfer liquid 24 left in the microdispenser 16. This protocol also results in washes to the internal surface of the glass capillary 62 and the external surface in the nozzle 63 area that was exposed to transfer liquid 24. The wash liquid can either be system liquid 20 or any other liquid placed onto the deck of the robotic system 58. The wash protocol is designed to minimize cross-contamination of different transfer liquids 24 used during different dispensing sessions. Towards this end, it is also possible to use a high frequency pulsing of the transducer 60 to facilitate washing of the microdispenser 16. This is accomplished using the control logic 42 to direct the microdispenser electronics 51 to send electrical pulses to the microdispenser at a frequency in the range of from about 1 to about 20 Khz (the preferred resonant frequency of the microdispenser 16 is believed to be approximately 12 kilohertz). The resonant frequency of the microdispenser coincides with the resonant frequency of the microdispenser 16—transfer liquid 24 system. Pulsing the piezoelectric transducer 60 at the above frequencies causes the interior surfaces of the glass capillary 62 to vibrate vigorously. System liquid 20, or a special cleaning and/or neutralizing liquid, is used to flush out the microdispenser 16 while the piezoelectric transducer 60 is activated at the above-described frequencies. Cleaning with high frequency pulsing is more efficient at dislodging and eliminating matter adhering to the microdispenser 16. For example, it has been shown in a number of test cases that such cleaning caused a 200 to 500% improvement (depending on the contaminant) in the reduction of residual matter in the microdispenser 16 compared to cleaning without such pulsing.
Pulsing of the microdispenser 16 is also used to prevent, minimize or alleviate clogging of the nozzle of the microdispenser. For example, when transfer liquid is being aspirated into the microdispenser 16, it must pass through the relatively narrow nozzle 63 in the glass capillary 62. Matter in the transfer liquid 24 often comes into contact with the nozzle's 63 surfaces, permitting the matter to adhere to the nozzle 63. In biochemical applications, one widely used matter added to the transfer liquid 24 is polystyrene spheres. These spheres typically range from 1 micron to over 30 microns, and may be uncoated or coated with magnetic ferrites, antigens or other materials. The relatively large size of the polystyrene spheres with regard to nozzle 63 diameter, in combination with their sometimes glutinous coatings, can cause the spheres to adhere to the nozzle 63. It has been discovered that if the piezoelectric transducer 60 is excited at high frequency while the microdispenser 16 is being loaded (i.e., transfer liquid 24 is being aspirated into the microdispenser 16), clogging is prevented or minimized. Thus, high frequency pulsing of the microdispenser 16 prevents or diminishes clogging of the nozzle 63 by materials in the transfer liquid 24.
Anytime a transfer liquid 24 containing dissolved or suspended materials passes through the nozzle 63, the possibility of clogging occurs. Not only is clogging a problem during aspiration of transfer liquid 24 into the microdispenser 16 as described above, but it is also a problem when transfer liquid is dispensed from the high frequency pulsing of the microdispenser 16. Droplet dispensing by the piezoelectric transducer can reduce buildup of materials adhering to the nozzle 63 and, thus, prevent clogging in some instances. Even if substantial clogging does occur, high frequency pulsing of the microdispenser 16 by the piezoelectric transducer 60 will substantially clear the clogging materials from the nozzle 63. The key advantage to this cleaning strategy is continuous instrument operation without the delays associated with alternate cleaning procedures. In short, system downtime is reduced, making the microvolume liquid handling system 10 more efficient.
In the above description of the invention, the control of the microdispenser 16 occurs via electrical pulses from the microdispenser electronics 51, with each pulse resulting in an emitted droplet 26 of transfer liquid 24. It is also within the scope of the invention to control the microdispenser 16 by monitoring the pressure sensor 14 signal in real time, and continuing to send electrical pulses to the microdispenser 16 until a desired change in pressure is reached. In this mode of operation, the PC-LPM-16 Multifunction I/O Board that contains the A/D converter 44 is instructed by control logic 42 to send electrical pulses to the microdispenser electronics 51. Each pulse sent by the Multifunction I/O Board results in one electrical pulse sent by the microdispenser electronics 51 to the microdispenser 16, emitting one droplet 26 of transfer liquid 24. The control logic 42 monitors the pressure sensor 14 signal as dispensing is in progress. Once the desired change in pressure has been attained, the control logic 42 directs the Multifunction I/O Board to discontinue sending electrical pulses.
This mode of operation is employed if a “misfiring” of microdispenser 16 has been detected by control logic 42.
It is also within the scope of the invention for the microvolume liquid handling system 10 to automatically determine the size of the emitted droplets 26 for transfer liquids 24 of varying properties. As heretofore mentioned, emitted droplet 26 size is affected by the properties of the transfer liquid 24. Therefore, it is desirable to be able to automatically determine emitted droplet 26 size so that the user need only specify the total transfer volume to satisfy the user requirements. In the encoded autocalibration algorithm, once the system 10 is primed, an air gap 22 and transfer liquid 24 are aspirated, and the control logic 42 instructs the microdispenser electronics 51 to send a specific number of electrical pulses, e.g., 1000, to the microdispenser 16. The resulting drop in pressure sensor 14 signal is used by the control logic 42 to determine the volume of transfer liquid 24 that was dispensed. The control logic verifies the volume of liquid dispersed by tracking the volume displaced by the movement of the plunger 34. The system subsequently restores the liquid line pressure to the pre-dispense value.
The microvolume liquid handling system 10 illustrated in FIG. 1 depicts a single microdispenser 16, pressure sensor 14, and pump 12. It is within the spirit and scope of this invention to include embodiments of microvolume liquid handling systems that have a multiplicity (e.g., 4, 8, 96) of microdispensers 16, pressure sensors 14, and pumps 12. It is also within the spirit and scope of this invention to include embodiments of microvolume liquid handling systems that have a multiplicity of microdispensers 16, pressure sensors 14, valves 38, and one or more pumps 12.
Description of a Second Aspirating and Dispensing Apparatus
In FIG. 7, another aspirating and dispensing apparatus 210 is shown. This embodiment, which is preferred when the number of microdispensers employed is equal to or greater than eight, also realizes the aforementioned objectives. The second apparatus is similar to the first shown in FIG. 1, except that the positive displacement pump (which includes a valve as described below), the stepper motor, and the piezoresistive pressure sensor are replaced with a pressure control system for supplying and controlling system liquid pressure. This embodiment also employs a plurality of flow sensors for detecting liquid flow, as well as pressure in the system liquid which is present in the connecting tubing that is coupled to each microdispenser. It also employs a plurality of valves (such as solenoid or microfabricated valves), each valve coupling each microdispenser to a system reservoir in the pressure control system. In this apparatus, a system liquid reservoir 214 is used to supply system liquid 20 to all the microdispensers 212, thus eliminating the separate pump and pressure sensor for each microdispenser 212 utilized in the first apparatus. Note that first and second embodiments are otherwise identical in structure and operation except as described herein. The precise number of microdispensers employed is a function of the user's dispensing requirements.
With regard to the second embodiment, the system liquid reservoir 214 receives system liquid 20, typically deionized water or dimethyl sulfoxide (DMSO), through an intake tube 216 which contains a cap (not separately shown). The cap on the intake tube 216 is removed to enable the sealed system liquid reservoir 214 to receive system liquid 20 when the cap is off, and seals the system liquid reservoir 214 shut when the cap is on so that the system liquid reservoir 214 can be maintained at a desired pressure. Pressure in the system liquid reservoir 214 is maintained by a pressure control system 218 through the use of pressure control tubing 220. The pressure control system 218 includes an electrically controlled pump capable of accurately increasing or decreasing pressure in the system liquid reservoir 214. A pressure sensor 222 mounted on the system liquid reservoir 214 senses pressure in the system liquid reservoir 214 and transmits an electrical signal indicative of that pressure to a system controller 224 through an electrical conductor 226. The system controller 224 contains a digital signal processor board and other electronics (not shown) which enable monitoring of various electrical signals, execution of control software code, and control of the microvolume liquid handling system 210. The system adjusts the pressure of the system liquid 20 and, correspondingly, the pressure of the transfer liquid 24 via an electrical conductor. A pressure relief valve 230 is mounted on the system liquid reservoir 214. The pressure relief valve 230 releases pressure from the system liquid reservoir 214 when the pressure exceeds a predetermined safety threshold. In one embodiment, the pressure relief valve 230 can also be opened by the system controller 224 which is connected to the pressure relief valve 230 by a wire 232.
During operations, the system controller 224 directs the pressure control system 218 to maintain one of three different pressure levels in the system reservoir 214 with regard to ambient atmospheric pressure. Each of the three pressure levels corresponds to a different phase of operation of the microvolume liquid handling system 210. The three different pressure levels include a positive pressure, a high negative pressure, and a low negative pressure. Prior to dispensing, positive pressure is used to clean the microdispenser. High frequency pulsing of the microdispensers 212 is also employed in the manner described above. After the microdispensers 212 are relatively clean, the high negative pressure levels (roughly 200 millibars less than the ambient atmospheric pressure) is used to aspirate transfer liquid 24 into the microdispensers 212. Once the transfer liquid 24 has been aspirated into the microdispensers 212, the low negative pressure levels (roughly −15 millibars gauge) are used to supply back pressure to the transfer liquid 24 in the microdispensers 212 such that as droplets are dispensed, no additional transfer liquid 24 leaves the microdispensers 212.
System liquid 20 in the system reservoir 214 is coupled to the microdispensers 212 through a distribution tube 234 that splits into a plurality of sections 236, as shown in FIG. 7, with one section 236 connected to each microdispenser 212. Attached to each of the distribution tube sections 236 are solenoid valves 242 and flow sensors 244. The system controller 224 sends electrical signals through an electrical connection 246 to control the valves 242. A flow sensor 244 is attached to each distribution tube section 236 to determine the amount of liquid that is being aspirated into each microdispenser. The flow sensor 244 detects the flow of system liquid 20 into or out of each microdispenser 212. The flow sensors 244 are each connected to the system controller 224 through an electrical conductor 248. The electrical conductor 248 carries electrical signals from each flow sensor 244, indicating not only the amount of liquid flow, but also the pressure in each flow sensor. The flow sensors 244 are microfabricated. This is advantageous since the sensors are small and fit easily into the microvolume liquid handling system 210. An example of the flow sensors 244 is described in IEEE Proceedings, MEMS 1995, Publication No. 0-7803-2503-6, entitled, “A Differential Pressure Liquid Flow Sensor For Flow Regulation and Dosing Systems,” by M. Boillat et al., hereby incorporated by reference.
The distribution tube 234, which is physically connected to the microdispensers 212, is attached to a three axis robot 238. As in the first preferred embodiment, the microdispensers are relocated to positions above different microtiter plates, wells or wafers. After the desired number of droplets has been dispensed, the robot 238 moves the microdispensers 212 to the next set of wells or wafers for further dispensing. The dispensing heads can be stationary and the robotic system can be used to locate the source and destination vessels.
It has been discovered that the ejection of individual drops of a transfer liquid in the volume range of about 100 to about 500 picoliters can be detected using the system of the present invention with a pressure detector. In order to detect dispensing of such drops, the transfer and system liquids must be substantially free of compressible gases, such as air. As used herein, the term “substantially free of compressible gas” means that the level of compressible gas, if any, is low enough to allow the detection of a drop of liquid being ejected from the system. It has been discovered that as the amount of compressible gas in the system increases, the ability to detect dispensing of the drop decreases until, at a certain level of compressible gas, the system cannot detect dispensing of a drop of the transfer liquid.
In accordance with one embodiment of the present invention, the volume from the dispensing nozzle, which holds the transfer liquid to the valve (242 in FIG. 8), is substantially free of compressible gas and is entirely enclosed. It has been discovered that in this preferred embodiment of the present invention, drops can be ejected from the closed volume until the pressure in the fluid is reduced to about −45 millibars gauge. At about −45 millibars gauge the vacuum interferes with the ejection of the drops.
In accordance with another embodiment of the present invention, the volume from the dispensing nozzle to the reservoir of system liquid is substantially free of compressible fluid (gas). It has been discovered that upon dispensing a drop of liquid, the system of this embodiment can detect a pressure change in the system liquid resulting from such drop being dispensed. The pressure change is transient. As the transfer liquid flows into the volume adjacent to the nozzle, effectively replacing the ejected drop volume, the pressure rises to the level prior to the dispensing of the drop. It has been discovered that for dispensing drops in the size range of from about 100 to about 500 picoliters, the time required for the pressure to reach the original level can be in a range of from about 5 to about 10 milliseconds. This time period can be controlled by selecting the size and confirmation of the orifice located between the volume that is adjacent to the nozzle and the reservoir. It has been determined that purging the air out of the system with a fluid (gas) that has a high solubility coefficient with respect to the system liquid has greatly reduced the residual compressible fluid (gas) in the system after priming with system liquid. Once the system is primed, keeping compressible fluids (e.g., air) out of the system is facilitated by degassing the system liquid, pressurizing the system liquid reservoir with an inert gas, utilizing low permeability tubing, and also degassing system liquid in-line. To aid in elimination of air bubbles, carbon dioxide purging can be employed as described in IEEE Proceedings, MEMS 1995, Publication No. 0-7803-2503-6, entitled “Carbon Dioxide Priming Of Micro Liquid Systems,” by R. Zengerle et al.
An example of the ability of the system to dispense single drops is provided in parent application Ser. No. 09/056,233, U.S. Pat. No. 6,203,759, and illustrated in FIGS. 8-11.
In accordance with another aspect of the present invention, several methods have been developed to minimize the amount of transfer liquid that needs to be aspirated into the dispenser. In the system of the present invention, which is capable of monitoring the ejection of single drops, the dispensing chamber has to be free of compressible fluids (gas) in order for the drops to be ejected. This requires that the chamber from the nozzle (63 in FIG. 3) to the top of the piezoelectric transducer (60 in FIG. 3) be filled with liquid. This volume is often large in comparison to the is volume of transfer liquid to be dispensed.
In accordance with one method, the system liquid and the transfer liquid are not separated from each other by an air gap, as shown in FIG. 1. Instead, the two liquids are separated by a liquid which is immiscible with either or both the transfer liquid and the system liquid.
In accordance with another method, to minimize the required aspirate volume of transfer liquid, system liquid is used to fill the dispenser before aspiration of the transfer liquid begins. It has been discovered that, as the transfer liquid is aspirated, the system liquid mixes with the transfer liquid at the interface slowly enough to allow dispensing of a large percentage of the transfer liquid without observing a dilution of the transfer liquid with the system liquid.
In embodiments which do not require use of a separate system liquid, a single liquid can be used to serve as both the system liquid and the transfer liquid.
In accordance with a further aspect of the present invention, the pressure in the dispenser (such as in dispenser 212 of FIG. 7) decreases as a result of a reduction in the system liquid reservoir (214 in FIG. 7) pressure. The valve (242 in FIG. 7) is closed, and then the nozzle of the dispensing unit can be immersed in the transfer liquid to aspirate a small quantity of the transfer liquid into the dispenser. For example, when gauge pressure in the dispenser reaches −30 millibars, submersing the nozzle in the transfer liquid may draw a sufficient amount of liquid to increase the gauge pressure to −15 millibars. It should be noted that the dispenser does not aspirate air unless the surface tension in the nozzle is exceeded by the negative gauge pressure. In the system of the preferred embodiment using dimethyl sulfoxide, the negative gauge pressure of 45 millibars does not produce air aspiration into the nozzle.
The systems described can automatically detect when the microdispenser orifice enters into a liquid and when it is withdrawn.
A pressure-based liquid detection function has been developed for the embodiments shown in FIGS. 1 and 7. This function can be used to detect when one or more micro dispensers is immersed in or withdrawn from liquid. This determination is made based on a pressure change which occurs when the microdispensers are immersed in or withdrawn from liquid. This pressure change is measured by monitoring the pressure transducer (14 in FIG. 1) or flow sensors (244 in FIG. 7). This test is performed independently for each system microdispenser.
The liquid determination process can be divided into three distinct stages.
Upon receipt of a “liquid level sense” command, the algorithm allows for a user-specified predelay to be performed. The duration of the delay allows the completion of an external event (i.e., the movement of the head to an aspiration source) to occur before the software begins to look for the pressure change of an air/liquid transition. Certain external events may result in a false positive if these events trigger a pressure change. This function allows the system to identify any spurious pressure change.
In the event that the predelay is zero, the software will begin monitoring the pressure immediately upon receipt of the “liquid level sense” command. This can also be applied in systems where the microdispensers are stationary and the robotic system moves the source, or aspiration vessel.
2. Baseline Establishment
Once the predelay has expired, a baseline pressure value is established from the average of multiple readings. This baseline pressure value will then be compared to subsequent pressure readings to determine if they differ enough to indicate an air-liquid transition.
3. Liquid Detect
The last stage is utilized to compare the established baseline pressure value with the current pressure values. The current pressure value is a rolling average. This ensures that a single spurious point will not result in an incorrect liquid detection event. During this stage, the pressure is read periodically. The oldest pressure value is then removed, the newest pressure value added, and a new average calculated. This average is then compared with the baseline which was established in the previous stage. The difference between these values is assessed via a user-specified threshold value. If the magnitude of the difference is greater than the threshold, then the algorithm will conclude that a liquid detect event has occurred and will set the liquid detected states to the control logic. The same test is performed independently for each dispenser.
The algorithm will continue to monitor the system for liquid detection events until a user-specified detection duration has expired. If no pressure transition of the specified magnitude occurs during this duration, the software will notify the control logic that no air-liquid transition has occurred for that particular dispenser.
The user-specified threshold value, in units of millibar, is used to refine the liquid detection process. If true air-liquid transitions are occurring, but are not being identified, then the threshold value can be decreased, thus enhancing detection sensitivity. If false liquid-detection determinations are being made as a result of random pressure fluctuations, the threshold value can be increased, thus diminishing detection sensitivity. The pressure threshold has a positive or negative value associated with it, thus enabling the user to activate the liquid detection function when the microdispensers are either immersed in or withdrawn from liquid.
Dispensing Drops of Liquid Onto a Porous Site
It has been discovered that liquid can be aspirated and small drops of liquid can be accurately dispensed onto porous sites of a wafer, forming uniform spots that are only slightly larger than the diameter of the drops. The drops of the liquid can range of from about 5 to about 500 picoliters. Depending on the application, a single drop or plurality of drops can be dispensed onto a single site. The wafer can contain distinctly defined porous sites, or its entire surface can be porous. The pores of the site should be smaller than the diameter of the drop, preferably about 10 to about 10,000 times smaller than the diameter of the drop. The drops are ejected from an outlet, which is separated from the reaction site by a distance larger than the diameter of the drop being dispensed. Since the drop does not touch the surface of the wafer prior to being dispensed, the combined properties of the liquid and the surface of the wafer do not affect the size of the drop. Upon coming into contact with the porous site, the drop forms a spot which is only slightly larger than the diameter of the drop (generally less than about 20% larger). Since the drops can be accurately deposited onto specific sites of the wafer and they form spots that are uniform and nearly the same size as the diameter of the drop, the sites can be closely spaced on a wafer.
The process of depositing droplets on porous substrates is generally illustrated in FIGS. 4-6. FIG. 4 illustrates the pattern of spots on a porous substrate, which provides a plurality of reaction sites. The sharply defined spots permit many reaction sites to be used for a unit area without cross-contamination of the liquids deposited. Actual results are shown in FIGS. 8-9 and discussed in Examples 1 and 2 below.
FIG. 5 illustrates a single drop being expelled from a microdispenser tip onto a porous substrate. The narrow pores extend normal to the plate of the surface so that the liquid droplet can be absorbed without spreading. Typically, the distances between the tip of the microdispenser and the wafer will be about 0.5 to 2 mm.
FIG. 6 illustrates the absorption of a drop into the porous substrate.
The dispensing of single, uniform drops in the sub-nanoliter range drop can be detected, quantified, and verified in real time. The system of the present invention is capable of automatically sensing liquid surfaces, aspirating liquid to be transferred, and then dispensing small quantities of liquid with high accuracy, speed and precision. The system of the present invention is pulsed at high frequency to prevent or eliminate clogging. Immiscible liquids between the transfer liquid and the system liquid can be used to reduce the required amount of transfer liquid needed for dispensing.
The following examples further illustrate the present invention and are not intended to limit the scope of the present invention in any manner.
The commercial version of the dispenser described in the present application, marketed under the trademark BioChip Arrayer™, was used to deposit liquid drops onto an Anapore membrane marketed by Whatman International Ltd. The drops ejected by the BioChip Arrayer were about 85 microns and included fluorescent material.
Twenty-seven drops were deposited as shown in FIG. 9. The fluorescence of the drops was compared and the results are shown in FIG. 10.
As shown in FIG. 9, the spots of the 27 drops were uniform with respect to each other. As shown in FIG. 10, the fluorescence emitted from the spots was generally uniform. The fluorescent signal was significantly higher only on the first 2 of the 27 spots.
BioChip Arrayer™ was used to deposit a plurality of drops of liquid onto an Anapore membrane. The drops contained fluorescent material and were about 85 microns in size. The resulting spots on the Anapore membrane are shown in FIG. 8, at 100× and 200×magnification. As shown in FIG. 8, the spots were uniform in size, measuring approximately 107 microns in diameter.
While the present invention has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments, and obvious variations thereof, is contemplated as falling within the spirit and scope of the claimed invention, which is set forth in the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3427480||16 Jun 1966||11 Feb 1969||Sonoptics Corp||Piezoelectric cleaning device|
|US3452360||28 Jul 1967||24 Jun 1969||Gen Precision Systems Inc||High-speed stylographic apparatus and system|
|US3507269||26 Apr 1965||21 Apr 1970||Homer H Berry||Clinical diagnostic device for halitosis|
|US3512173||28 Dec 1967||12 May 1970||Xerox Corp||Alphanumeric ink droplet recorder|
|US3549328||29 Nov 1967||22 Dec 1970||Us Health Education & Welfare||Test paper for detector of niacin|
|US3666421||5 Apr 1971||30 May 1972||Organon||Diagnostic test slide|
|US3683212||9 Sep 1970||8 Aug 1972||Clevite Corp||Pulsed droplet ejecting system|
|US3711252||13 Oct 1971||16 Jan 1973||A Roy||Composition and method for the detection of uric acid|
|US3798961||17 Feb 1972||26 Mar 1974||C Flambard||Apparatus for non-destructive checking of workpieces|
|US3831845||17 Aug 1973||27 Aug 1974||Partek Corp Of Houston||Fluid delivery system|
|US3832579||7 Feb 1973||27 Aug 1974||Gould Inc||Pulsed droplet ejecting system|
|US3838012||20 Nov 1972||24 Sep 1974||Lilly Co Eli||Multipoint test paper|
|US3859169||30 Apr 1973||7 Jan 1975||Polymeric Enzymes Inc||Enzymes entrapped in gels|
|US3902083||12 Oct 1973||26 Aug 1975||Gould Inc||Pulsed droplet ejecting system|
|US3946398||29 Jun 1970||23 Mar 1976||Silonics, Inc.||Method and apparatus for recording with writing fluids and drop projection means therefor|
|US3958249||18 Dec 1974||18 May 1976||International Business Machines Corporation||Ink jet drop generator|
|US3964871||18 Dec 1974||22 Jun 1976||Becton, Dickinson And Company||Method and device for detecting glucose|
|US3975162||13 Mar 1974||17 Aug 1976||Marine Colloids, Inc.||Applying reagent to medium and device therefor|
|US3985467||27 May 1975||12 Oct 1976||Milton Roy Company||Constant pressure pump|
|US3994423||25 Nov 1974||30 Nov 1976||American Hospital Supply Corporation||Drop dispensing apparatus for laboratory reagents|
|US3996006||28 Apr 1976||7 Dec 1976||Smithkline Corporation||Specimen test slide|
|US4038570||26 Jan 1976||26 Jul 1977||Durley Iii Benton A||Ultrasonic piezoelectric transducer drive circuit|
|US4046513||30 Jun 1976||6 Sep 1977||Miles Laboratories, Inc.||Printed reagent test devices and method of making same|
|US4084165||29 Nov 1976||11 Apr 1978||Siemens Aktiengesellschaft||Fluid-jet writing system|
|US4087332||22 Jul 1977||2 May 1978||Kai Aage Hansen||Indicator for use in selection of bactericidal and bacteristatic drugs and method for producing same|
|US4193009||7 Nov 1977||11 Mar 1980||Durley Benton A Iii||Ultrasonic piezoelectric transducer using a rubber mounting|
|US4216245||25 Jul 1978||5 Aug 1980||Miles Laboratories, Inc.||Method of making printed reagent test devices|
|US4223558||24 Nov 1978||23 Sep 1980||Beckman Instruments, Gmbh||Pipetting and diluting apparatus|
|US4234103||31 Mar 1978||18 Nov 1980||Baxter Travenol Laboratories, Inc.||Diagnostic reagent dispensing bottle|
|US4241406||21 Dec 1978||23 Dec 1980||International Business Machines Corporation||System and method for analyzing operation of an ink jet head|
|US4278983||23 May 1979||14 Jul 1981||Gould Inc.||Ink jet writing device|
|US4293867||6 May 1980||6 Oct 1981||Ricoh Co., Ltd.||Device for removing air bubbles formed and trapped in ink chamber of print head of ink-jet printer|
|US4298345||30 Mar 1979||3 Nov 1981||Damon Corporation||Method and apparatus for chemical spot test analysis|
|US4308546||5 Nov 1979||29 Dec 1981||Gould Inc.||Ink jet tip assembly|
|US4341310||3 Mar 1980||27 Jul 1982||United Technologies Corporation||Ballistically controlled nonpolar droplet dispensing method and apparatus|
|US4366490||19 Feb 1982||28 Dec 1982||Exxon Research And Engineering Co.||Method and apparatus for tuning ink jets|
|US4410020||26 Mar 1981||18 Oct 1983||Contraves Ag||Sensor syringe|
|US4418356||23 Sep 1981||29 Nov 1983||Ncr Corporation||Ink jet print head|
|US4426031||26 Aug 1981||17 Jan 1984||Gould Inc.||Method of soldering ink jet nozzle to piezoelectric element|
|US4447375||11 Jul 1983||8 May 1984||Siemens Aktiengesellschaft||Method of casting a printing head for an ink jet printer|
|US4492322||30 Apr 1982||8 Jan 1985||Indiana University Foundation||Device for the accurate dispensing of small volumes of liquid samples|
|US4498088||22 Jul 1982||5 Feb 1985||Sharp Kabushiki Kaisha||Ink jet air bubble detection|
|US4503012||19 Apr 1983||5 Mar 1985||American Monitor Corporation||Reagent dispensing system|
|US4504845||17 Aug 1983||12 Mar 1985||Siemens Aktiengesellschaft||Piezoelectric printing head for ink jet printer, and method|
|US4512722||18 Oct 1983||23 Apr 1985||Societe Nationale d'Etude de Constudies de Mateurs d'Aviation||Device and process for monitoring cavitation in a positive displacement pump|
|US4514743||9 Apr 1984||30 Apr 1985||Nixdorf Computer Ag||Ink jet filtered-chamber print head|
|US4518974||21 Sep 1982||21 May 1985||Ricoh Company, Ltd.||Ink jet air removal system|
|US4530463||5 Aug 1982||23 Jul 1985||Hiniker Company||Control method and apparatus for liquid distributor|
|US4539575||23 May 1984||3 Sep 1985||Siemens Aktiengesellschaft||Recorder operating with liquid drops and comprising elongates piezoelectric transducers rigidly connected at both ends with a jet orifice plate|
|US4548825||3 Oct 1983||22 Oct 1985||Boehringer Ingelheim Gmbh||Method for ink-jet printing on uncoated tablets or uncoated tablet cores|
|US4550325||26 Dec 1984||29 Oct 1985||Polaroid Corporation||Drop dispensing device|
|US4600928||12 Apr 1985||15 Jul 1986||Eastman Kodak Company||Ink jet printing apparatus having ultrasonic print head cleaning system|
|US4633413||28 Jul 1983||30 Dec 1986||Cavro Scientific Instruments||Digital dilution apparatus and method|
|US4646104||17 Sep 1985||24 Feb 1987||Eastman Kodak Company||Fluid jet print head|
|US4651161||17 Jan 1986||17 Mar 1987||Metromedia, Inc.||Dynamically varying the pressure of fluid to an ink jet printer head|
|US4672398||31 Oct 1985||9 Jun 1987||Hitachi Ltd.||Ink droplet expelling apparatus|
|US4681741||17 Dec 1986||21 Jul 1987||American Hospital Supply Corporation||Reagent dispenser for an analyzing system|
|US4682710||15 Apr 1986||28 Jul 1987||Nordson Corporation||Multi-station viscous liquid distribution system|
|US4691850||9 Aug 1984||8 Sep 1987||Kirschmann John D||Chemical dispensing system|
|US4695852||23 Oct 1986||22 Sep 1987||Ing. C. Olivetti & C., S.P.A.||Ink jet print head|
|US4701754||18 Apr 1985||20 Oct 1987||Fmc Corporation||Indicator device for substance receiving wells in a microtiter plate|
|US4777832||14 Nov 1986||18 Oct 1988||Chemila S R L||Liquid level sensor, used in an automatic station for preparing immunologic dosages|
|US4877745||14 Mar 1989||31 Oct 1989||Abbott Laboratories||Apparatus and process for reagent fluid dispensing and printing|
|US4934419||30 Nov 1988||19 Jun 1990||Analytical Instruments Limited||Fleet data monitoring system|
|US4976259||2 Nov 1988||11 Dec 1990||Mountain Medical Equipment, Inc.||Ultrasonic nebulizer|
|US5039614||15 Jun 1990||13 Aug 1991||Armenag Dekmezian||Method and apparatus for collecting samples for analysis of chemical composition|
|US5055263||14 Jan 1988||8 Oct 1991||Cyberlab, Inc.||Automated pipetting system|
|US5059393||5 Jan 1989||22 Oct 1991||Eastman Kodak Company||Analysis slide positioning apparatus and method for a chemical analyzer|
|US5072235||26 Jun 1990||10 Dec 1991||Xerox Corporation||Method and apparatus for the electronic detection of air inside a thermal inkjet printhead|
|US5141871||10 May 1990||25 Aug 1992||Pb Diagnostic Systems, Inc.||Fluid dispensing system with optical locator|
|US5225750||26 Sep 1990||6 Jul 1993||Prima Meat Packers, Ltd.||Microinjection apparatus, and method of controlling microinjection|
|US5229679||3 May 1991||20 Jul 1993||Prima Meat Packers, Ltd.||Microdrive apparatus|
|US5232664||18 Sep 1991||3 Aug 1993||Ventana Medical Systems, Inc.||Liquid dispenser|
|US5252294||3 Feb 1992||12 Oct 1993||Messerschmitt-Bolkow-Blohm Gmbh||Micromechanical structure|
|US5297734||11 Oct 1991||29 Mar 1994||Toda Koji||Ultrasonic vibrating device|
|US5306510||1 Feb 1991||26 Apr 1994||Cyberlab, Inc.||Automated pipetting system|
|US5334353||3 Feb 1993||2 Aug 1994||Blattner Frederick R||Micropipette device|
|US5356034||22 Jan 1993||18 Oct 1994||Boehringer Mannheim Gmbh||Apparatus for the proportioned feeding of an analysis fluid|
|US5365783||30 Apr 1993||22 Nov 1994||Packard Instrument Company, Inc.||Capacitive sensing system and technique|
|US5378962||29 May 1992||3 Jan 1995||The United States Of America As Represented By The Secretary Of The Navy||Method and apparatus for a high resolution, flat panel cathodoluminescent display device|
|US5415679||20 Jun 1994||16 May 1995||Microfab Technologies, Inc.||Methods and apparatus for forming microdroplets of liquids at elevated temperatures|
|US5449345||30 Mar 1994||12 Sep 1995||Merit Medical Systems, Inc.||Detachable and reusable digital control unit for monitoring balloon catheter data in a syringe inflation system|
|US5453091||5 Apr 1994||26 Sep 1995||Merit Medical Systems, Inc.||RF transmission module for wirelessly transmitting balloon catheter data in a syringe inflation system|
|US5457527||30 Mar 1994||10 Oct 1995||Packard Instrument Company, Inc.||Microplate forming wells with transparent bottom walls for assays using light measurements|
|US5485828||28 Apr 1993||23 Jan 1996||Hauser; Jean-Luc||Portable device for micropulverization generated by ultrasound waves|
|US5525515||1 Aug 1994||11 Jun 1996||Blattner; Frederick R.||Process of handling liquids in an automated liquid handling apparatus|
|US5527707||20 Dec 1994||18 Jun 1996||Kabushiki Kaisha Toshiba||Method of analyzing impurities in the surface of a semiconductor wafer|
|US5529754||11 Apr 1995||25 Jun 1996||Hoffmann-La Roche Inc.||Apparatus for capacitatively determining the position of a pipetting needle within an automated analyzer|
|US5543827||11 Apr 1994||6 Aug 1996||Fas-Co Coders, Inc.||Ink jet print head nozzle cleaning coinciding with nozzle vibration|
|US5554339||19 Aug 1993||10 Sep 1996||I-Stat Corporation||Process for the manufacture of wholly microfabricated biosensors|
|US5620004||23 Oct 1995||15 Apr 1997||Johansen; Aaron||Airway indicator device|
|US5630793||23 Mar 1995||20 May 1997||Zeneca Limited||Aqueous ophthalmic sprays|
|US5651648||22 Feb 1996||29 Jul 1997||Virginia Tech Intellectual Properties, Inc.||Method for reducing ceramic tool wear and friction in machining/cutting applications|
|US5653726||13 May 1996||5 Aug 1997||Archimedes Surgical, Inc.||Retrograde dissector and method for facilitating a TRAM flap|
|US5655446||19 Jul 1994||12 Aug 1997||Riso Kagaku Corporation||Stencil printing plate having a soluble resin layer|
|US5658723||23 May 1994||19 Aug 1997||Cardiovascular Diagnostics, Inc.||Immunoassay system using forced convection currents|
|US5658802||7 Sep 1995||19 Aug 1997||Microfab Technologies, Inc.||Method and apparatus for making miniaturized diagnostic arrays|
|US5659173||23 Feb 1994||19 Aug 1997||The Regents Of The University Of California||Converting acoustic energy into useful other energy forms|
|US5661245||14 Jul 1995||26 Aug 1997||Sensym, Incorporated||Force sensor assembly with integrated rigid, movable interface for transferring force to a responsive medium|
|US5663754||5 Sep 1995||2 Sep 1997||Xerox Corporation||Method and apparatus for refilling ink jet cartridges|
|US5673073||14 Mar 1996||30 Sep 1997||Hewlett-Packard Company||Syringe for filling print cartridge and establishing correct back pressure|
|US5674238||24 Jun 1996||7 Oct 1997||Research Foundation Of The State Univ. Of N.Y.||Perineometer|
|US5675367||14 Mar 1996||7 Oct 1997||Hewlett-Packard Company||Inkjet print cartridge having handle which incorporates an ink fill port|
|US5681757 *||29 Apr 1996||28 Oct 1997||Microfab Technologies, Inc.||Process for dispensing semiconductor die-bond adhesive using a printhead having a microjet array and the product produced by the process|
|US5682236||2 Jul 1993||28 Oct 1997||Metrolaser||Remote measurement of near-surface physical properties using optically smart surfaces|
|US5685310||10 Oct 1995||11 Nov 1997||The Board Of Regents Of The University Of Nebraska||Suspended ultra-sound microbubble imaging|
|US5685848||7 Jun 1995||11 Nov 1997||Scimed Life Systems, Inc.||Balloon catheter inflation device|
|US5690907||8 Jun 1995||25 Nov 1997||The Jewish Hospital Of St. Louis||Avidin-biotin conjugated emulsions as a site specific binding system|
|US5691478||7 Jun 1995||25 Nov 1997||Schneider/Namic||Device and method for remote zeroing of a biological fluid pressure measurement device|
|US5693016||8 Nov 1995||2 Dec 1997||Gumaste; Anand V.||Solid state fluid delivery system|
|US5694919||27 Oct 1995||9 Dec 1997||Aradigm Corporation||Lockout device for controlled release of drug from patient-activated dispenser|
|US5694946||23 Jun 1994||9 Dec 1997||Radi Medical Systems Ab||Method for in vivo monitoring of physiological pressures|
|US5695457||7 Dec 1994||9 Dec 1997||Heartport, Inc.||Cardioplegia catheter system|
|US5695461||27 Sep 1996||9 Dec 1997||Schaible; Eric R.||Ophthalmic instrument for fracturing and removing a cataract and a method for using the same|
|US5695468||16 Jan 1996||9 Dec 1997||Scimed Life Systems, Inc.||Balloon catheter with improved pressure source|
|US5695740||30 May 1995||9 Dec 1997||The Board Of Regents Of The University Of Nebraska||Perfluorocarbon ultrasound contrast agent comprising microbubbles containing a filmogenic protein and a saccharide|
|US5697375||24 Jan 1995||16 Dec 1997||The Research Foundation Of State University Of New York||Method and apparatus utilizing heart sounds for determining pressures associated with the left atrium|
|US5698018||29 Jan 1997||16 Dec 1997||Eastman Kodak Company||Heat transferring inkjet ink images|
|US5700848||7 Jun 1995||23 Dec 1997||Vivorx Inc.||Gel compositions prepared from crosslinkable polysaccharides, polycations and/or lipids and uses therefor|
|US5701899||31 May 1995||30 Dec 1997||The Board Of Regents Of The University Of Nebraska||Perfluorobutane ultrasound contrast agent and methods for its manufacture and use|
|US5702384||2 Jun 1995||30 Dec 1997||Olympus Optical Co., Ltd.||Apparatus for gene therapy|
|US5763278||1 Nov 1995||9 Jun 1998||Tecan Ag||Automated pipetting of small volumes|
|US5843767||10 Apr 1996||1 Dec 1998||Houston Advanced Research Center||Microfabricated, flowthrough porous apparatus for discrete detection of binding reactions|
|US5877580 *||23 Dec 1996||2 Mar 1999||Regents Of The University Of California||Micromachined chemical jet dispenser|
|US5916524||23 Jul 1997||29 Jun 1999||Bio-Dot, Inc.||Dispensing apparatus having improved dynamic range|
|US5927547||12 Jun 1998||27 Jul 1999||Packard Instrument Company||System for dispensing microvolume quantities of liquids|
|US6015820||30 Jul 1996||18 Jan 2000||Centre National De La Recherche Scientifique (Cnrs)||4-Aryl-thio-pyridin-2(1H)-ones, medicines containing them and their uses in the treatment of illnesses linked to HIV|
|US6063339||3 Sep 1998||16 May 2000||Cartesian Technologies, Inc.||Method and apparatus for high-speed dot array dispensing|
|US6083762||16 Jan 1998||4 Jul 2000||Packard Instruments Company||Microvolume liquid handling system|
|US6203759||7 Apr 1998||20 Mar 2001||Packard Instrument Company||Microvolume liquid handling system|
|US6244575 *||2 Oct 1996||12 Jun 2001||Micron Technology, Inc.||Method and apparatus for vaporizing liquid precursors and system for using same|
|US6280148 *||5 Feb 1998||28 Aug 2001||Hahn-Schickard-Gesellschaft Fur Angewandte Forschung||Microdosing device and method for operating same|
|DE3007189C2||26 Feb 1980||4 Jun 1992||Xerox Corp., Rochester, N.Y., Us||Title not available|
|DE3014256A1||14 Apr 1980||11 Dec 1980||Xerox Corp||Mit piezowandler betriebene fluessigkeitstroepfchen-abgabevorrichtung|
|DE3332491C2||8 Sep 1983||10 Oct 1985||Siemens Ag, 1000 Berlin Und 8000 Muenchen, De||Title not available|
|DE3833586A1||3 Oct 1988||13 Jul 1989||Medizin Labortechnik Veb K||Method for the volumetrically correct delivery of liquids in the microlitre range|
|DE3915920A1||16 May 1989||22 Nov 1990||Messerschmitt Boelkow Blohm||Micro-mechanical structures for storing and testing substances - e.g. for disease diagnosis, is made of inert material, e.g. glass, and has defined pattern of depressions, cavities, etc.|
|DE4140533A1||9 Dec 1991||17 Jun 1993||Voegele Ag J||Lubricant micro-dispensation with pressure variation by piezoelectric transducer used in e.g. ink-jet printer - delivers very small droplets at intervals determined by pulsed connection of platelet transducer to voltage source|
|DE19532382A1||1 Sep 1995||6 Mar 1997||Max Planck Gesellschaft||Analyser for chemical or physical changes in fluids|
|EP0012821B1||8 Nov 1979||18 May 1983||International Business Machines Corporation||Ink jet printer with means for monitoring its ink jet head-operation|
|EP0024230A1||31 Jul 1980||25 Feb 1981||COMMISSARIAT A L'ENERGIE ATOMIQUE Etablissement de Caractère Scientifique Technique et Industriel||Device for dispensing microquantities of liquid|
|EP0072558A3||16 Aug 1982||12 Feb 1986||Tecan AG||Method and automatic apparatus for pipetting|
|EP0119573A1||12 Mar 1984||26 Sep 1984||Miles Laboratories, Inc.||Microdroplet dispensing apparatus and method|
|EP0169071B1||18 Jul 1985||23 Jan 1991||EASTMAN KODAK COMPANY (a New Jersey corporation)||Apparatus and method for detecting liquid penetration by a container used for aspirating and dispensing the liquid|
|EP0202022A3||10 Apr 1986||7 Oct 1987||John Raymond Wells||Hydraulic dispenser|
|EP0219177B1||15 Oct 1986||28 Mar 1990||Philips Patentverwaltung GmbH||Method and apparatus for applying droplets of adhesive to a surface|
|EP0268237B1||16 Nov 1987||12 Oct 1994||Abbott Laboratories||Apparatus and process for reagent fluid dispensing and printing|
|EP0412431B1||2 Aug 1990||29 Oct 1997||Becton Dickinson and Company||Method and apparatus for sorting particles with a moving catcher tube|
|EP0432992B1||10 Dec 1990||25 Aug 1993||Bespak plc||Dispensing apparatus|
|EP0433992B1||18 Dec 1990||16 Mar 1994||Sumitomo Electric Industries, Ltd.||Method of forming metallized layer on aluminium nitride sintered body|
|EP0438136A3||16 Jan 1991||22 Jan 1992||Mochida Pharmaceutical Co., Ltd.||Automated dispensing and diluting system|
|EP0446972B1||24 Jan 1991||27 Aug 1997||Akzo Nobel N.V.||Device and methods for detecting microorganisms|
|EP0508531B1||2 Apr 1992||25 Oct 1995||Johnson & Johnson Clinical Diagnostics, Inc.||Liquid dispensing using container bottom sensing|
|EP0513441A1||30 Dec 1991||19 Nov 1992||Hewlett-Packard Company||Orificeless printhead for an ink jet printer|
|EP0545284B1||26 Nov 1992||5 Feb 1997||Canon Kabushiki Kaisha||Sample measuring device and sample measuring system|
|EP0548872B1||21 Dec 1992||25 Jun 1997||Cardiovascular Dynamics, Inc.||Ultrasonic flow sensing assembly|
|EP0568024B1||27 Apr 1993||16 Jul 1997||Canon Kabushiki Kaisha||Micropump and measuring cartridge utilizing same|
|EP0581708B1||26 Jul 1993||5 Nov 1997||Advanced Cardiovascular Systems, Inc.||Automated fluid pressure control system|
|EP0628413B1||11 Nov 1991||25 Mar 1998||Citizen Watch Co. Ltd.||Ink jet head|
|EP0655256A3||25 Nov 1994||11 Oct 1995||Minnesota Mining & Mfg||Inhaler.|
|EP0712232B1||14 Nov 1995||13 May 1998||Riso Kagaku Corporation||Plate-making method and apparatus for stencil sheet|
|EP0718046B1||10 Dec 1990||12 Jul 2000||Bespak plc||Dispensing apparatus|
|EP0747689B1||6 Jun 1996||23 Jan 2002||Medical Laboratory Automation, Inc.||Liquid aspiration from a sealed container|
|EP0761256A3||12 Aug 1996||23 Sep 1998||Programmable Pump Technologies Inc.||Power supply for implantable device|
|EP0763742B1||31 May 1995||2 Apr 2008||Kanagawa Academy Of Science And Technology||Optical fiber and its manufacture|
|EP0766946A3||21 Aug 1996||2 May 1997||Graphic Controls Corporation||Transducer-tipped intrauterine pressure catheter system|
|EP0779436A3||6 Dec 1996||28 Jul 1999||Frank T. Hartley||Micromachined peristaltic pump|
|EP0781987A3||27 May 1994||9 Jul 1997||FISONS plc||Analytical apparatus|
|EP0788809B1||13 Dec 1996||3 May 2006||TECNIMED S.r.l.||A portable device for treating insect bites and the like|
|EP0789383B1||31 Jan 1997||2 Jul 2008||Canon Kabushiki Kaisha||Method of manufacturing electron-emitting device, electron source and image-forming apparatus and method of examining the manufacturing|
|EP0795409B1||13 Mar 1997||15 Dec 1999||Hewlett-Packard Company||Printing systems|
|EP0799436B2||31 Aug 1996||11 Sep 2002||Uwe Maass||Use of an image projector for displaying moving images in the background of a stage|
|EP0810096B1||13 Dec 1993||3 Apr 2002||Canon Kabushiki Kaisha||Ink jet recording apparatus using recording unit with ink cartridge having ink inducing element|
|EP0810438B1||30 May 1997||4 Feb 2004||Packard Instrument Company, Inc.||Microvolume liquid handling system|
|ES2073992B1||Title not available|
|JP1038147B||Title not available|
|JP1150549A||Title not available|
|JP2017079B||Title not available|
|JP5579167B2||Title not available|
|RU2011961C1||Title not available|
|1||Ashley et al. "Development and Characterization of Ink for an Electrostatic Ink Jet Printer" pp. 69-74, IBM J. Res. Develop. (Undated).|
|2||Beach et al., "Materials Selection for an Ink Jet Printer" pp. 75-86, IBM J. Res. Develop. (Undated).|
|3||Boillat et al., "A Differential Pressure Liquid Flow Sensor for Flow Regulation and Dosing Systems," Proceedings IEEE, Micro Electro Mechanical Systems, MEMS, '95 Amsterdam.|
|4||Buehner, et al., "Application of Ink Jet Technology to a Word Processing Output Printer", pp. 1-9, IBM J. Res. Develop. (Undated).|
|5||Carmichael, "Controlling Print Height in an Ink Jet Printer" pp. 52-55, IBM J. Res. Develop. (Undated).|
|6||Curry, Portig, "Scale Model of an Ink Jet", pp. 10-20, IBM J. Res. Develop. (Undated).|
|7||Filmore et al. Drop Charging and Deflection in an Electrostatic Ink Jet Printer, pp. 37-47, IBM J. Res. Develop. (Undated).|
|8||Holcombe, Eklund & Grice, "Vaporization and Atomization of Large Particles in an Acetylene/Air Flame", pp. 2097-2103, Analytical Chemistry, vol. 50, No. 14, Dec. 1978.|
|9||J.M. Köhler et al., "Micromechanical elements for detection of molecules and molecular design", pp. 202-208, Microsystem Technologies, Springer-Verlag 1995.|
|10||Joshi and Sacks "Circular Slot Burner-Droplet Generator System for High-Temperature Reaction and Vapor Transport Studies" pp. 1781-1785, Analytical Chemistry, vol. 51, No. 11, Sep. 1979.|
|11||Lee "Boundary Layer Around a Liquid Jet" pp. 48-51, IBM J. Res. Develop. (Undated).|
|12||Levanoni, "Study of Fluid flow through Scaled-up Ink Jet Nozzles" pp. 56-68, IBM J. Res. Develop. (Undated).|
|13||Microdrop Instruction Manual, Microdrop Gesellschaft für Mikrodosiersysteme mbH, AD-E-130, Sep. 1995.|
|14||Microdrop Instruction Manual, Microdrop Gesellschaft für Mikrodosiersysteme mbH, MD-K-130SP/140H/135/150 and Drive electronics MD-E-204, May 1994.|
|15||Microdrop Literature, "Flussigkeiten mikrofein dosieren" Gesellschaft for Mikrodosiersysteme mbH, 1994 (in the German language).|
|16||Microdrop literature, "Microdosing in the picoliter range with piezo technology" sales brochure from Microdrop Gesellschaft für Mickrodosiersysteme mbH, Oct. 1995.|
|17||Pimbley "Satellite Droplet Formation in a Liquid Jet" pp. 21-30, Satellite Formation, IBM J. Res. Develop. (Undated).|
|18||Plunkett, Matthew J. et al., "Combinatorial Chemistry and New Drugs," Scientific American, Apr. 1997, p. 69-73.|
|19||Schober, A., et al., "Accurate High-Speed Liquid Handling of Very Small Biological Samples," BioTechniques, vol. 15, No. 2 (1993), p, 324-329.|
|20||Twardeck "Effect of Parameter Variations on Drop Placement in an Electrostaic Ink Jet Printer" pp. 31-36, IBM J. Res. Develop. (Undated).|
|21||Zengerle et al., "Carbon Dioxide Priming of Micro Liquid Systems," IEEE (1995), pp. 340-343.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US6709872 *||2 May 2000||23 Mar 2004||Irm Llc||Method and apparatus for dispensing low nanoliter volumes of liquid while minimizing waste|
|US6913933 *||3 Dec 2001||5 Jul 2005||Ortho-Clinical Diagnostics, Inc.||Fluid dispensing algorithm for a variable speed pump driven metering system|
|US7125521 *||26 Apr 2004||24 Oct 2006||Taiwan Semiconductor Manufacturing Company, Ltd.||Method to solve alignment mark blinded issues and technology for application of semiconductor etching at a tiny area|
|US7160511 *||16 Feb 2001||9 Jan 2007||Olympus Corporation||Liquid pipetting apparatus and micro array manufacturing apparatus|
|US7258253 *||30 Apr 2004||21 Aug 2007||Aurora Discovery, Inc.||Method and system for precise dispensation of a liquid|
|US7276380 *||30 Jul 2001||2 Oct 2007||Matsushita Electric Industrial Co., Ltd.||Transparent liquid inspection apparatus, transparent liquid inspection method, and transparent liquid application method|
|US7402286 *||15 Dec 2004||22 Jul 2008||The Regents Of The University Of California||Capillary pins for high-efficiency microarray printing device|
|US7407630||22 Mar 2005||5 Aug 2008||Applera Corporation||High density plate filler|
|US7998435||30 Mar 2006||16 Aug 2011||Life Technologies Corporation||High density plate filler|
|US8015939||30 Jun 2006||13 Sep 2011||Asml Netherlands B.V.||Imprintable medium dispenser|
|US8079278||21 Jul 2006||20 Dec 2011||Board Of Trustees Of Michigan State University||End effector for nano manufacturing|
|US8220502 *||28 Dec 2007||17 Jul 2012||Intermolecular, Inc.||Measuring volume of a liquid dispensed into a vessel|
|US8231828||20 Nov 2006||31 Jul 2012||Hitachi, Ltd.||Small size gene analysis apparatus|
|US8246908||21 Feb 2007||21 Aug 2012||Hitachi Ltd.||Small size gene analysis apparatus|
|US8277760||30 Mar 2006||2 Oct 2012||Applied Biosystems, Llc||High density plate filler|
|US8283181||9 Jul 2008||9 Oct 2012||The Regents Of The University Of California||Capillary pins for high-efficiency microarray printing device|
|US8307722||19 May 2006||13 Nov 2012||Universal Bio Research Co., Ltd.||Method of detecting dispensed quantity, and liquid suction monitoring dispensing apparatus|
|US8323882||9 Jul 2010||4 Dec 2012||Biodot, Inc.||Method and system for the analysis of high density cells samples|
|US8333936 *||19 Jan 2011||18 Dec 2012||Hitachi Plant Technologies, Ltd.||Reagent splitting/dispensing method based on reagent dispensing nozzle and reagent splitting/dispensing mechanism|
|US8475741 *||14 Sep 2010||2 Jul 2013||Postech Academy-Industry Foundation||Droplet discharging device|
|US8486485||29 Jul 2011||16 Jul 2013||Asml Netherlands B.V.||Method of dispensing imprintable medium|
|US8528608 *||8 Jun 2012||10 Sep 2013||Intermolecular, Inc.||Measuring volume of a liquid dispensed into a vessel|
|US8545757 *||18 Jan 2010||1 Oct 2013||Hitachi High-Technologies Corporation||Automatic analyzer and sample treatment apparatus|
|US8893923||28 Nov 2012||25 Nov 2014||Intermolecular, Inc.||Methods and systems for dispensing different liquids for high productivity combinatorial processing|
|US8900530 *||22 Nov 2004||2 Dec 2014||Capitalbio Corporation||Micro-volume liquid ejection system|
|US8920752||1 Feb 2013||30 Dec 2014||Biodot, Inc.||Systems and methods for high speed array printing and hybridization|
|US8940478||3 Dec 2012||27 Jan 2015||Accupath Diagnostic Laboratories, Inc.||Method and system for the analysis of high density cells samples|
|US9068566||20 Jan 2012||30 Jun 2015||Biodot, Inc.||Piezoelectric dispenser with a longitudinal transducer and replaceable capillary tube|
|US9415369||23 Dec 2014||16 Aug 2016||Accupath Diagnostic Laboratories, Inc.||Method and system for the analysis of high density cells samples|
|US20020037239 *||24 Sep 2001||28 Mar 2002||Fuji Photo Film Co., Ltd.||Quantitative suction tip and quantitative suction apparatus|
|US20020106308 *||2 Feb 2001||8 Aug 2002||Zweifel Ronald A.||Microdrop dispensing apparatus|
|US20020151042 *||30 Jul 2001||17 Oct 2002||Teruaki Fukuyama||Transparent liquid testing apparatus, transparent liquid testing method, and transparent liquid coating method|
|US20030104634 *||3 Dec 2001||5 Jun 2003||Orthoclinical Diagnostics, Inc.||Fluid dispensing algorithm for a variable speed pump driven metering system|
|US20030215957 *||27 May 2003||20 Nov 2003||Tony Lemmo||Multi-channel dispensing system|
|US20040185569 *||23 Dec 2003||23 Sep 2004||Zweifel Ronald A.||Controlling microdrop dispensing apparatus|
|US20040198017 *||26 Apr 2004||7 Oct 2004||Taiwan Semiconductor Manufacturing Company||Method to solve alignment mark blinded issues and technology for application of semiconductor etching at a tiny area|
|US20040265185 *||22 Apr 2004||30 Dec 2004||Olympus Corporation||Method of washing liquid pipetting apparatus and dispensing head|
|US20050006417 *||30 Apr 2004||13 Jan 2005||David Nicol||Method and system for precise dispensation of a liquid|
|US20050095723 *||4 Nov 2003||5 May 2005||Drummond Scientific Company||Automatic precision non-contact open-loop fluid dispensing|
|US20050220675 *||22 Mar 2005||6 Oct 2005||Reed Mark T||High density plate filler|
|US20050225751 *||22 Mar 2005||13 Oct 2005||Donald Sandell||Two-piece high density plate|
|US20050226782 *||22 Mar 2005||13 Oct 2005||Reed Mark T||High density plate filler|
|US20050232820 *||22 Mar 2005||20 Oct 2005||Reed Mark T||High density plate filler|
|US20050232821 *||22 Mar 2005||20 Oct 2005||Carrillo Albert L||High density plate filler|
|US20050233363 *||31 Mar 2005||20 Oct 2005||Harding Ian A||Whole genome expression analysis system|
|US20060102803 *||30 Sep 2004||18 May 2006||Wheaton James M||Leading edge flap apparatuses and associated methods|
|US20060233670 *||30 Mar 2006||19 Oct 2006||Lehto Dennis A||High density plate filler|
|US20060233671 *||30 Mar 2006||19 Oct 2006||Beard Nigel P||High density plate filler|
|US20060233672 *||30 Mar 2006||19 Oct 2006||Reed Mark T||High density plate filler|
|US20060233673 *||30 Mar 2006||19 Oct 2006||Beard Nigel P||High density plate filler|
|US20060272738 *||30 Mar 2006||7 Dec 2006||Gary Lim||High density plate filler|
|US20070014694 *||22 Mar 2005||18 Jan 2007||Beard Nigel P||High density plate filler|
|US20070053798 *||7 Nov 2006||8 Mar 2007||Innovadyne Technologies, Inc.||Universal non-contact dispense peripheral apparatus and method for a primary liquid handling device|
|US20070122310 *||20 Nov 2006||31 May 2007||Hitachi Ltd.||Small size gene analysis apparatus|
|US20070155019 *||26 Jan 2007||5 Jul 2007||Innovadyne Technologies, Inc.||System and method for repetitive, high performance, low volume, non-contact liquid dispensing|
|US20070264666 *||26 Jul 2007||15 Nov 2007||Applera Corporation||High density sequence detection methods|
|US20070289992 *||2 Oct 2006||20 Dec 2007||Aurora Discovery, Inc.||Method and system for precise dispensation of a liquid|
|US20080003827 *||30 Jun 2006||3 Jan 2008||Asml Netherlands B.V.||Imprintable medium dispenser|
|US20080227663 *||18 Jan 2008||18 Sep 2008||Biodot, Inc.||Systems and methods for high speed array printing and hybridization|
|US20080267828 *||22 Nov 2004||30 Oct 2008||Capitalbio Corporation||Micro-Volume Liquid Ejection System|
|US20090029876 *||9 Jul 2008||29 Jan 2009||The Regents Of The University Of California||Capillary pins for high-efficiency microarray printing device|
|US20090074625 *||2 Dec 2008||19 Mar 2009||Innovadyne Technologies, Inc.||Micro fluidics manifold apparatus|
|US20090087344 *||21 Feb 2007||2 Apr 2009||Hitachi, Ltd.||Small size gene analysis apparatus|
|US20090211380 *||19 May 2006||27 Aug 2009||Universal Bio Research Co., Ltd.||Method of Detecting Dispensed Quantity, and Liquid Suction Monitoring Dispensing Apparatus|
|US20090217508 *||21 Jul 2006||3 Sep 2009||Board Of Trustees Of Michigan State University||End Effector for Nano Manufacturing|
|US20090223012 *||21 Sep 2007||10 Sep 2009||Fujifilm Corporation||Liquid suction device|
|US20100273680 *||9 Jul 2010||28 Oct 2010||Accupath Diagnostic Laboratories, Inc. (D.B.A. U.S. Labs)||Method and system for the analysis of high density cells samples|
|US20100300433 *||27 May 2010||2 Dec 2010||Alexza Pharmaceuticals, Inc.||Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol|
|US20110176975 *||19 Jan 2011||21 Jul 2011||Hitachi Plant Technologies, Ltd.||Reagent splitting / dispensing method based on reagent dispensing nozzle and reagent splitting / dispensing mechanism|
|US20120039771 *||18 Jan 2010||16 Feb 2012||Hitachi High-Technologies Corporation||Automatic analyzer and sample treatment apparatus|
|US20120196374 *||9 Apr 2012||2 Aug 2012||Beckman Coulter, Inc.||Dispenser, analyzer and dispensing method|
|US20120219468 *||14 Sep 2010||30 Aug 2012||Postech Academy-Industry Foundation||Droplet discharging device|
|US20120273072 *||8 Jun 2012||1 Nov 2012||Intermolecular, Inc.||Measuring volume of a liquid dispensed into a vessel|
|US20130025690 *||29 Jul 2011||31 Jan 2013||Intermolecular, Inc.||No-Contact Wet Processing Tool with Liquid Barrier|
|CN1975376B||27 Nov 2006||8 Dec 2010||株式会社日立制作所||Small size gene analysis apparatus|
|CN104969077A *||24 Oct 2013||7 Oct 2015||阿尔特贡股份公司||Method and device for measuring and controlling the dosage of small quantities of fluid by means of a resonating needle, and resonating needle suitable for this purpose|
|EP1714116A1 *||6 Feb 2004||25 Oct 2006||Seyonic SA||Pipette verification device and pipette|
|EP1714116A4 *||6 Feb 2004||26 Mar 2008||Seyonic Sa||Pipette verification device and pipette|
|EP1790415A1 *||13 Nov 2006||30 May 2007||Hitachi, Ltd.||Small size gene analysis apparatus|
|EP1873587A2 *||20 Jun 2007||2 Jan 2008||ASML Netherlands BV||Inprintable medium dispenser|
|EP1882951A1 *||19 May 2006||30 Jan 2008||Universal Bio Research Co., Ltd.||Method of detecting dispensed quantity, and liquid suction monitoring dispensing apparatus|
|EP1882951A4 *||19 May 2006||7 Sep 2011||Universal Bio Research Co Ltd||Method of detecting dispensed quantity, and liquid suction monitoring dispensing apparatus|
|EP2037283A4 *||19 Jun 2007||8 Jul 2015||Beckman Coulter Inc||Dispensing device and automatic analysis device|
|EP2218505A1 *||13 Nov 2006||18 Aug 2010||Hitachi, Ltd.||Small size gene analysis apparatus|
|EP2374542A1 *||13 Nov 2006||12 Oct 2011||Hitachi, Ltd.||Small size gene analysis apparatus|
|WO2007014095A2 *||21 Jul 2006||1 Feb 2007||Board Of Trustees Of Michigan State University||End effector for nano manufacturing|
|WO2007014095A3 *||21 Jul 2006||5 Apr 2007||Univ Michigan State||End effector for nano manufacturing|
|WO2014064641A2||24 Oct 2013||1 May 2014||Altergon Sa||Method and device for measuring and controlling the dosage of small quantities of fluid by means of a resonating needle, and resonating needle suitable for this purpose|
|WO2014064641A3 *||24 Oct 2013||12 Jun 2014||Altergon Sa||Method and device for measuring and controlling the dosage of small quantities of fluid by means of a resonating needle, and resonating needle suitable for this purpose|
|U.S. Classification||422/504, 73/863.01, 222/333, 436/180, 222/406, 222/309, 73/863.02, 222/263|
|International Classification||B01L3/02, C40B60/14, G01F1/48, G01N35/10, G01N35/00, G01F3/00|
|Cooperative Classification||B01J2219/00659, G01F3/00, B01J2219/00612, B01J2219/00596, B01J2219/00605, G01N2035/1018, G01N2035/1025, B01J2219/00691, B01L3/0268, G01N2035/1041, B01J2219/00527, G01N2035/1039, C40B60/14, B01J2219/00689, B01J2219/0063, B01J2219/0061, G01F1/48, Y10T436/2575, G01N2035/1034, B01J2219/00378, G01N35/1016, G01N35/1065, G01N2035/00237|
|European Classification||G01N35/10M, G01F1/48, B01L3/02D10, G01F3/00|
|23 Jun 2000||AS||Assignment|
Owner name: PACKARD INSTRUMENT COMPANY, ILLINOIS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PAPEN, ROELAND F.;REEL/FRAME:010956/0241
Effective date: 20000602
|4 Aug 2006||FPAY||Fee payment|
Year of fee payment: 4
|18 Aug 2010||FPAY||Fee payment|
Year of fee payment: 8
|18 Aug 2014||FPAY||Fee payment|
Year of fee payment: 12